The Aim of this application is to characterize peripheral and central pain mechanisms relevant for clinical pain in subjects with fibromyalgia syndrome (FM). Because tonic nociceptive muscle input may play an important role for chronic pain and hyperalgesia in FM and other musculoskeletal pain syndromes, a careful psychophysical characterization of the response of FM subjects to muscle manipulations could provide crucial support of this hypothesis. The first Specific Aim of this application will characterize the mechanical and thermal hyperalgesia of FM and NC subjects in relation to carefully controlled tonic pain manipulation of muscles. We posit that local spontaneous pain in FM is strongly indicative of local and widespread thermal and mechanical hyperalgesia. In addition, we will test the role of experimental manipulations of peripheral tonic nociceptive input on clinical pain and local/widespread hyperalgesia of FM subjects by applying sustained mechanical pressure to tender muscles (tonic nociceptive input). We posit that clinical pain and cutaneous/muscle pain sensitivity will more markedly increase following tonic muscle stimulation in FM compared to NC subjects, and these effects will be particularly prolonged for FM subjects. We will compare the results of mechanical and thermal test stimuli obtained during baseline testing with those obtained after the muscle stimulation, An increase of adjacent and possibly of distant secondary hyperalgesia relative to the manipulated muscle area would support the role of tonic muscle nociceptive input for hyperalgesia and clinical pain of FM subjects. In the second Specific Aim we will study the analgesic mechanisms of FM subjects related to injections of lidocaine or saline placebo into painful trapezius muscle (TrapM) tender points (analgesia). We posit that local lidocaine/saline placebo injection into one TrapM tender point will have several effects;a) it will reduce muscle hyperalgesia (primary) and local pain after injection;b) it will reduce the secondary cutaneous hyperalgesia of FM subjects within adjacent and distant body areas;c) it will reduce general clinical FM pain. We will compare the response to thermal and mechanical test stimuli obtained during baseline testing with those obtained after the muscle injections. We will carefully estimate the contribution of the placebo effect by comparing the natural history (no analgesic intervention) to saline placebo and lidocaine injections during tonic painful muscle stimuli. Importantly, the study design will provide clinically relevant information about the relative contribution of peripheral analgesic mechanisms (i.e. anesthesia of peripheral sources of algesic input) and placebo analgesic mechanisms to local and general reductions in FM pain. We posit: a) Intramuscular lidocaine injections will produce larger reductions in local and generalized pain than will saline placebo injections and b) the variance in placebo responses will be strongly associated with ratings of expected pain intensities and desire for pain reduction, consistent with our previous work. Although it is possible that placebo factors alone are sufficient to produce reductions in both clinical pain and hyperalgesia and may account for some, most, or even all of the variance in therapeutic effects from muscle injections, our preliminary data showed superior effectiveness of lidocaine injections. Thus, such findings would be of considerable clinical and mechanistic significance, because they would corroborate previous work showing considerable effects of lidocaine on hyperalgesic states and provide estimates of their magnitude. In the third Specific Aim we will evaluate the placebo effects of analgesic manipulations (lidocaine or saline placebo) on experimental and clinical pain. We posit that a) manipulations designed to increase the placebo effect (verbal suggestions) will enhance the analgesic efficacy of lidocaine and saline injections;b) the magnitude of the placebo effect is predicted by expectations and desire for pain relief. Characterization of the placebo effect will provide important information on analgesic mechanisms related to muscle injections. Thus our application will not only provide strong evidence for or against the role of tonic nociceptive input from muscles as a relevant mechanism for clinical pain and hyperalgesia of FM patients but also delineate the analgesic mechanisms (central, peripheral, or both) that are operant during injections of painful muscles. Either way, we will provide evidence that will characterize the role of local anesthesia, placebo analgesia, or both. Thus patients with FM and other similar pain syndromes may strongly benefit from the results of our study.